The interleukin-1beta converting enzyme (caspase-1 or caspase-1) cell death gene family, also known as the caspase family, plays an important role in apoptosis. Evidence indicates that caspase- 1 is involved in mediating brain damange in ischemia, trauma, and in amyotrophic lateral sclerosis. We have evidence implicating caspase-1 as an important mediator of cell dysfunction and disease progression in Huntington s disease (HD). The broad objective of this project is to evaluate the mechanisms of caspase-1-mediates disease progression in HD. Preliminary results indicate that caspase-1 is activated in human and mouse HD brain specimens. In addition, inhibiting caspase function slows the progression and delays the mortality in a mouse model of HD. The specific aims are: 1) evaluate the expression and activation status of different members of the caspase family in human and mouse HD brain specimens, 2) evaluate the role of mature IL-1beta, a product of caspase-1 activation, in the pathogenesis of HD, 3) determine whether bc1-2 might be a neuroprotector in HD, and whether its effects might be synergistic with caspase-1 inhibition, 4) evaluate pharmacological approaches to slow the progression of HD, and 5) evaluate the mechanism of inhibition of weight loss in HD mice by caspase-1 inhibition, 6) evaluate the impact of HD on neural stem cell proliferation and differentiation. Significance: To elucidate the mechanistic pathways by which caspase-1 mediates disease progression and death in HD. Since caspase-1-mediated cell death is a common pathway shared by a variety of neurological disorders, understanding the mechanistic pathways mediating neurodegeneration in HD should provide important information for the development of treatments for diseases sharing this cell death pathway.